Biomedical Applications of Polysaccharide-based Stimuli-responsive Hydrogels

The biomedical field is constantly looking for new biomaterials with innovative properties, and natural polymers are good candidates for this matter having in view their unique properties (Silva et al. 2012). From this large group of natural polymers, polysaccharides in particular have received increasing attention in biomedical and pharmaceutical fields due to natural abundance, their unique chemical structures and physicochemical/biological properties, and the ability to form hydrogels (Chan 2009).

Hydrogels derived from natural occurring polysaccharides are high-water content polymeric materials that possess a number of favourable properties for biomedical applications (Salgueiro et al. 2013). The hydrogels’ desired characteristics depend on the application: in wound healing, the ability to absorb wound exudates is very important, along with oxygen transport to the wound site; in tissue engineering, the ability to mimic the extracellular matrix and support cell growth is sought; in drug delivery, soft and rubbery consistency and low interfacial tension with water and biological fluids are considered as excellent characteristics (O’Connor et al. 2018; Fu et al. 2018).

Stimuli-Responsive Hydrogels in Drug Delivery Systems

The primary goals in development of drug delivery systems are to protect an active therapeutic molecule from premature degradation, enhance drug efficiency by prolonging in vivo drug actions and reducing its metabolism rate, and also minimize its side effects by reducing some possible drug toxicity (Sharpe et al. 2014; Fajardo et al. 2015). Oral drug delivery is the ideal administration route that involves low costs (Nokhodchi et al. 2012) and is desirable for a diversity of therapeutics for treatment of both systemic and local diseases. Unfortunately, this is limited only to conventional small-molecule drugs. For macro-molecular drugs, such as peptides, proteins, and chemotherapeutics, which suffer poor stability in the gastro-intestinal tract, being subject to enzymatic degradation, acidic denaturation, low solubility, and absorption, innovative drug delivery systems are required (Sharpe et al. 2014). Over the last few decades, extensive researches related to the hydrogels used in drug delivery have been made, being encouraged by their biocompatible properties and easy control of solute transport (Jeong et al. 2012).

The hydrogel-based drug delivery systems are generally of two types: time-con- trolled systems and stimuli-induced release systems. The last category of responsive hydrogel systems is designed to deliver the drugs in response to a variable condition so that it can fulfill its requirements at the right time and place (Das and Pal 2015). Characteristics like the swelling behaviour in an aqueous medium, external stimuli sensitivity, and zero-order kinetics play important roles in the development of hydro- gel-based drug delivery systems (Dumitriu et al. 2009; Fu et al. 2018). In the last decades, huge progresses have been made in the use of polysaccharides to obtain stable and versatile hydrogels to be applied as carriers for drug delivery (Fajardo et al. 2015; Kumar et al. 2018) and the wide variety of polysaccharides response stimuli make them particularly attractive in this field (Alvarez-Lorenzo et al. 2013).

Thermo-Responsive Hydrogels in Drug Delivery

Temperature-sensitive hydrogels are probably the most commonly studied class of environment-sensitive polymer systems in drug delivery applications (Shen et al. 2016). Many natural polymers have been shown to exhibit gelation when temperature changes. They can be used alone or in combination with synthetic polymers to obtain thermally responsive hydrogels with desired properties (Klouda and Mikos 2008).

Cellulose-based thermo-responsive hydrogels. Cellulose-based materials have become very popular in recent years in obtaining stimuli-sensitive hydrogels due to their versatility, renew'ability, relatively low cost, abundance, and extensive study of these bio-polymers (Kumar et al. 2018). Cellulose derivatives have been extensively investigated for biomedical applications in drug delivery.

Methylcellulose (MC), the simplest cellulose derivative, exhibits thermo-reversible gelation properties in aqueous solutions: it gels on heating at temperature values between 60 and 80°C and turns into solution upon cooling. But this gelling temperature is found to be too high for biomedical applications, so methylcellulose is grafted with synthetic N-isopropylacrylamide (NIPAM) resulting in hydrogels which combine the thermo-gelling properties of both materials, in addition to improved mechanical characteristics due to methylcellulose (Klouda and Mikos 2008).

Carboxymethylcellulose (CMC), which is another functional derivative of cellulose, is capable of forming thermo-responsive hydrogels. The drug delivery system based on carboxymethyl cellulose and gelatin showed sol-gel transition near the body temperature and was used for transdermal drug therapy with lidocaine for treatment of atopic dermatitis. These hydrogels have provided both moisture and drug to the skin, protecting pathogenesis of atopic dermatitis (Chatterjee and Hui 2018).

Hydroxypropylcellulose (HPC) is a derivative of cellulose and a biodegradable, biocompatible macromolecule. HPC shows a well-defined LCST in water at about 41°C. According to its unique hydrophilic/hydrophobic change, thermo-responsive НРС-based hydrogels have been prepared for controlled delivery of hydrophilic drugs. One advantage of HPC over many other synthetic thermally responsive macromolecules is that HPC has been approved by the United States Food and Drug Administration for the use in food, drug, and cosmetics (Zhang et al. 2011).

Chitosan-based thermo-responsive hydrogels. The chitosan-based drug delivery systems, in various chemical and physical gel forms, have been developed and studied in the past decades (Wu et al. 2006). Chitosan-based materials lack intrinsic thermo-sensitive properties. Thus, other thermo-sensitive materials need to be combined with chitosan to make it applicable as a thermo-sensitive hydrogel (Domalik- Pyzik et al. 2018). Chitosan-based thermo-sensitive hydrogels have been prepared by grafting chitosan (CS) with poly(N-isopropylacrylamide) (PNIPAM) (Lee et al. 2004; Wang et al. 2009; Chen et al. 2018), with polyethylene glycol) (PEG) (Kim et al. 2011), or mixing chitosan with poly(vinyl alcohol) (PVA) and sodium bicarbonate (Tang et al. 2007; Ji et al. 2009).

Grafting PNIPAM side chains on chitosan backbone is an expanding research field, as it combines the most studied thermo-sensitive polymer with the most outstanding cationic polysaccharide to achieve materials with remarkable properties. The drug-loading characteristics of the chitosan-g-PNIPAM hydrogel, obtained by direct grafting via free radical polymerization, were tested by Lee and co-workers (Lee et al. 2004) using caffeine as the model drug. The study has proved the ability of this hydrogel to function as a temperature-controlled drug delivery system, the loading amount of the model drug at 20°C being affected by increasing the chitosan/

PNIPAM weight ratio and cross-linking agent amount, and the release rate is controlled by pore size and hydrogel swelling ratio at 37°C. The ability of the PNIPAM/ chitosan semi-interpenetrating network hydrogel as controlled-release vehicles for pilocarpine hydrochloride, used in some ophthalmic diseases, was evaluated (Prabaharan and Mano 2006). The release process was found to be fast, with most of the drug being released in the first 40 min and the hydrogel loading/release properties were influenced by the chitosan proportion in the network.

A thermo-sensitive drug delivery vehicle using chitosan (CS), hyaluronic acid (HA), and synthetic PNIPAM was prepared and evaluated for controlled release of an analgesic drug called nalbuphine (Kim et al. 2011), proving the positive effect of CS/ HA hydrogels incorporated in PNIPAM network by greater control of the drug release in vitro compared to PNIPAM hydrogels alone.

The efficiency of PEG-grafted chitosan thermo-sensitive hydrogels has been proven as protein delivery vehicles, using albumin as a model protein. The test findings showed that protein release was rapid in the first three days, followed by constant, controlled release in the next three days (Kim et al. 2011).

The combination of carboxymethyl-chitosan (CMCS) and PNIPAM has been investigated as localized drug delivery system for anticancer and anti-inflammatory drugs. The drug molecules release is controlled by the PNIPAM grafting proportion, pH and temperature of the release medium. The cytocompatibility of these hydrogels has also been confirmed by mesenchymal stem cell culturing, all these data indicating the great potentials of these hydrogels as localized drug delivery systems (Zhang et al. 2014).

Dextran-based thermo-responsive hydrogels. Dextran has no thermo-sensitivity; therefore, other thermo-sensitive materials are added to form thermo-sensitive hydrogels. Dextran, being part of a polymer block next to oligolactate, 2-hydroxyethyl methacrylate (HEMA), and PNIPAM. are capable of forming thermo-sensitive hydrogels with LCST around 32°C and exhibiting temperature-controlled release of incorporated albumin (Kim et al. 2011). The multifunctional and biodegradable thermo-responsive hydrogels made from PNIPAM, dextran. and poly(L-lactic acid) (PLLA) were used as drug delivery systems, and it showed gelation (LCST) around 32°C (Chatterjee and Hui 2018).

Injectable thermo-sensitive hydrogels in drug deliverу systems. Injectable hydrogels are superior to preformed hydrogels, primarily due to their ability to fill and cover spaces of any shape and secondly because they do not require a surgical procedure for implantation (Upadhyay 2017). They have a very high affinity for body fluids and may be delivered into body through a catheter or by direct injection with a syringe (Figure 9.8) (Mathew et al. 2018). The high-water content, soft nature, pliability, and porous structure mimicking biological tissues of these injectable hydrogels are unique features minimizing mechanical irritation and damage to the surrounding tissues during subcutaneous administration. Stimuli-sensitive injectable hydrogels are able to switch sol-to-gel transitions, in aqueous solutions, in response to various stimuli including pH. temperature, light, enzyme, and magnetic field (Thambi et al. 2016). Polysaccharide-based injectable hydrogels are extremely advantageous and have a variety of biomedical applications in drug delivery and tissue engineering (Upadhyay 2017).

Application of injectable hydrogel systems in biomedical field.(Reprinted with permission from Mathew et al. 2018)

FIGURE 9.8 Application of injectable hydrogel systems in biomedical field.(Reprinted with permission from Mathew et al. 2018).

Injectable thermogel based on polyethylene glycol)-g-chitosan was synthesized, for drug release in vitro, using bovine serum albumin (BSA) as a model protein. In the release study, after an initial burst release in the first 5 h, a steady linear release of the protein from the hydrogel was achieved for a period of ~ 70 h. Prolonged quasi-linear release of protein up to 40 days was achieved by cross-linking the hydrogel with genipin in situ, in a fashion suitable for protein encapsulation, while maintaining the injectability of the hydrogel (Prabaharan and Mano 2006).

The thermo-sensitivity and rheological properties of injectable poly(vinyl alcohol)-chitosan hydrogels, formed by mixture of chitosan (CS), poly(vinyl alcohol) (PVA), and sodium bicarbonate was evaluated potentially as a drug release system using bovine serum albumin. PVA is frequently used as implant material for drug delivery systems and surgical repairs due to its excellent mechanical strength, biocompatibility, and nontoxicity. The hydrogel is liquid in aqueous solutions at low temperature (about 4°C) and forms gel implants in situ in response to increasing temperature to physiological value, when bioactive specie is safely and uniformly incorporated (Tang et al. 2007).

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